A case of erythropoietic protoporphyria with liver cirrhosis suggesting a therapeutic value of supplementation with Î±-tocopherol

Komatsu, Hirokazu; Ishii, Kohdoh; Imamura, Kazuyuki; Maruyama, Katsuya; Yasuda, Yoshikazu; Masuda, Hideaki; Tsuchihashi, Takeshi; Sajima, Yoshikiyo

doi:10.1016/s1386-6346(00)00077-2

Cited by 18 publications

(10 citation statements)

References 33 publications

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“…In agreement with observations in patients with EPP‐induced liver disease 28–31, variable amounts of PP deposition were present in hepatocytes, bile canaliculi, and lobular and portal macrophages, and in the lumen of small bile ducts of fch/fch mouse livers. Small bile ducts containing PP deposits had a flattened and damaged epithelium.…”

Section: Discussionsupporting

confidence: 89%

Liver pathology and hepatocarcinogenesis in a long‐term mouse model of erythropoietic protoporphyria

Libbrecht

Meerman

Kuipers³

et al. 2002

The Journal of Pathology

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Erythropoietic protoporphyria (EPP) is an inherited disease of haem synthesis caused by a mutation in one of the alleles of the enzyme ferrochelatase. This mutation leads to partial deficiency of the enzyme, resulting in increased concentrations of protoporphyrin (PP) in blood, liver, and faeces. Five to ten per cent of patients with EPP develop severe liver disease characterized by the presence of PP deposits. This study used histochemistry and immunohistochemistry to investigate the histopathological features present in the livers of 44 mice with a heterozygous or homozygous point mutation in the ferrochelatase gene (fch/+ and fch/fch mice, respectively). Some fch/+ mouse livers showed mixed steatosis and large cell dysplasia. The livers of fch/fch mice showed periportal or septal fibrosis accompanied by an atypical ductular reaction. These findings suggest that the obstruction and damage of a proportion of large and small bile ducts by PP deposits cause an accumulation of PP in the parenchyma, which leads to damage and loss of hepatocytes due to the toxic effects of PP. The classical stages of hepatocarcinogenesis were observed and hepatic progenitor cells appear to be involved in this process. PP acts as the promoting agent and is probably also the initiating agent.

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Section: Discussionsupporting

confidence: 89%

Liver pathology and hepatocarcinogenesis in a long‐term mouse model of erythropoietic protoporphyria

Libbrecht

Meerman

Kuipers³

et al. 2002

The Journal of Pathology

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“…54 62 c To reverse oxidative stress in EPP by intravenous vitamin E therapy. 63 One or more of these treatments are sometimes combined, 58 59 and this is currently the practice before liver transplantation in order to optimise the environment into which the new liver is transplanted. 64 65 However, none of these treatments is effective in all cases, each has potential problems and none has been applied in sufficient numbers of patients to allow a rigorous evaluation of efficiency.…”

Section: Cholelithiasismentioning

confidence: 99%

“…62 Finally, intravenous vitamin E was reported to be effective at reversing severe EPP-related liver disease in a single case report. 63 Terminal phase of EPP-associated liver disease Deteriorating liver disease in EPP is characterised by cholestasis 83 followed by jaundice and generalised upper abdominal pain. 66 The spleen becomes enlarged and haemolysis may ensue.…”

Section: Cholelithiasismentioning

confidence: 99%

Liver disease in erythropoietic protoporphyria: insights and implications for management

Anstey

Hift²

2007

Postgraduate Medical Journal

114

177

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“…Consequently, PPIX-mediated bile duct blockage results in cholestatic liver injury, which can further lead to fibrosis, cirrhosis and liver failure [7–10, 14]. Various treatments have been used to manage EPP-associated liver injury in clinical practice, such as suppressing PPIX production by iron therapy [15] or intravenous administration of hemin [16], reducing PPIX pool by plasmapheresis or hemodialysis [17], interrupting the enterohepatic circulation of PPIX by charcoal [18], increasing bile flow by chenodeoxycholic acid or ursodeoxycholic acid [19, 20], and inhibiting oxidative stress by vitamin E [21]. However, the efficiency of these approaches has not been proved in large numbers of patients and none of them is consistently effective in all cases [5, 9, 10].…”

Section: Introductionmentioning

confidence: 99%

Liver metabolomics in a mouse model of erythropoietic protoporphyria

Wang

Sachar

Guo

et al. 2018

Biochemical Pharmacology

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Erythropoietic protoporphyria (EPP) is a genetic disease that results from the defective mutation in the gene encoding ferrochelatase (FECH), the enzyme that converts protoporphyrin IX (PPIX) to heme. Liver injury and even liver failure can occur in EPP patients because of PPIX accumulation in the liver. The current study profiled the liver metabolome in an EPP mouse model caused by a Fech mutation (Fech-mut). As expected, we observed the accumulation of PPIX in the liver of Fech-mut mice. In addition, our metabolomic analysis revealed the accumulation of bile acids and ceramide (Cer) in the liver of Fech-mut mice. High levels of bile acids and Cer are toxic to the liver. Furthermore, we found that the major phosphatidylcholines (PC) in the liver and the ratio of total PC to PPIX in the bile were decreased in Fech-mut mice compared to wild type mice. A decrease of the ratio of PC to PPIX in the bile can potentiate the accumulation of PPIX in the liver because PC increases PPIX solubility and excretion. These metabolomic findings suggest that the accumulation of PPIX, together with the disruption of the homeostasis of bile acids, Cer, and PC, contributes to EPP-associated liver injury.

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A case of erythropoietic protoporphyria with liver cirrhosis suggesting a therapeutic value of supplementation with Î±-tocopherol

Cited by 18 publications

References 33 publications

Liver pathology and hepatocarcinogenesis in a long‐term mouse model of erythropoietic protoporphyria

Liver pathology and hepatocarcinogenesis in a long‐term mouse model of erythropoietic protoporphyria

Liver disease in erythropoietic protoporphyria: insights and implications for management

Liver metabolomics in a mouse model of erythropoietic protoporphyria

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